The pancreas produces digestive enzymes, as well as several important hormones, including insulin, glucagon and somatostatin. The hormone producing cells are grouped together in the Islets of Langerhans, which make up approximately 1 to 2% of the pancreas. In a healthy pancreas, insulin is produced by β-cells in the Islets of Langerhans in response to increased levels of blood glucose. There are a number of diseases that result from, or in, the loss of pancreatic tissue. These diseases include diabetes mellitus (both Type 1 and 2) and exocrine pancreatic insufficiency.
Type 1 diabetes (insulin-dependent diabetes mellitus) is an autoimmune disorder in which a body's immune system attacks the β-cells, destroying them or sufficiently damaging them such that little or no insulin is produced. Although insulin replacement therapy, strict diet and careful blood glucose monitoring can limit the complications associated with diabetes, it is desirable to replace or regenerate the pancreas.
Type 2 diabetes (non-insulin-dependent diabetes mellitus) is a metabolic disorder that is initially characterized by insulin resistance, but ultimately characterized by the failure of pancreatic β-cells to match insulin production with insulin demand.
Exocrine pancreatic insufficiency (EPI) is the inability to properly digest food due to a lack of digestive enzymes made by the pancreas. EPI is found in humans afflicted with cystic fibrosis and Shwachman-Diamond Syndrome. It is caused by a progressive loss of the pancreatic cells that make digestive enzymes. Chronic pancreatitis is the most common cause of EPI in humans. Loss of digestive enzymes leads to maldigestion and malabsorption of nutrients.
There is a need in the art to develop methods and medications for regenerating pancreatic tissue.
Surgical transplantation of the islets has not yet proven to be effective, but it is known that pancreatic cells have the ability to regenerate. Pancreas regeneration-promoting factors, such as HIP, INGAP, GLP-1, Exendin-4, have been investigated (e.g. WO 2006/096565, U.S. Pat. No. 6,114,307, and U.S. Pat. No. Re. 39,299).
Periostin is an approximately 90 kDa secreted protein, preferentially expressed in the periosteum in bone tissues. (Takeshita et al. (1993). Biochem. J., 294:271-8; Horiuchi et al. (1999). J. Bone Miner. Res., 14:1239-49). Periostin comprises an NH2-terminal secretory signal peptide, followed by a cysteine-rich domain, four internal homologous repeats, and a COOH-terminal hydrophilic domain. Within each repeat domain, two regions are highly conserved. Periostin has been identified in various cancers and its presence has been proposed as a marker and a therapeutic target for cancer (Kanno et al. (2008) Int. J. Cancer 122: 1707-18). Periostin has also been shown to be secreted by pancreatic stellate cells (PSCs) and perpetuate PSC fibrogenic activity while supporting pancreatic tumor cell growth under stress conditions (Erkan, et al. (2007) Gastroenterology 132:1447-64).